A Multi-Site Phase 3 Study of MDMA-Assisted Psychotherapy for PTSD (MAPP1)
Posttraumatic stress disorder (PTSD) is a debilitating psychiatric disorder that can develop after a traumatic life experience that severely reduces the quality of life. This multi-site, double-blind, placebo-controlled, randomized Phase III study assessed the efficacy and safety of MDMA-assisted psychotherapy compared to psychotherapy with placebo in participants diagnosed with at least moderate PTSD.
Detailed Description
This randomised, double-blind, parallel-group Phase 3 trial (n≈100) compared MDMA-assisted psychotherapy versus placebo with identical psychotherapy in adults with severe PTSD.
Participants received three preparatory psychotherapy sessions, three experimental sessions (MDMA 80 or 120 mg with a supplemental half-dose 1.5–2 hours later, or placebo), each experimental session followed by three integrative therapy sessions.
Primary outcome is change in CAPS-5 from baseline to 18 weeks; safety assessments include blood pressure, heart rate, body temperature, adverse events and C-SSRS for suicidal ideation/behaviour.
Study Protocol
Preparation
Dosing
Integration
Therapeutic Protocol
Study Arms & Interventions
MDMA-assisted therapy
experimentalThree experimental sessions of MDMA-assisted manualized therapy (plus preparatory and integrative sessions).
Interventions
- MDMA80 - 180 mgvia Oral• three sessions• 3 doses total
Initial 80 or 120 mg followed 1.5–2 h later by supplemental half-dose (40 or 60 mg); per-session total 80–180 mg.
Placebo with therapy
placeboThree experimental sessions of inactive placebo with identical manualized therapy.
Interventions
- Placebovia Oral• three sessions• 3 doses total
Inactive placebo administered during experimental sessions.
Participants
Inclusion Criteria
- Are at least 18 years old
- Are fluent in speaking and reading the predominantly used or recognized language of the study site
- Are able to swallow pills
- Agree to have study visits recorded, including Experimental Sessions, Independent Rater assessments, and non-drug psychotherapy sessions
- Must provide a contact (relative, spouse, close friend or other caregiver) who is willing and able to be reached by the investigators in the event of a participant becoming suicidal or unreachable.
- Must agree to inform the investigators within 48 hours of any medical conditions and procedures
- If of childbearing potential, must have a negative pregnancy test at study entry and prior to each Experimental Session, and must agree to use adequate birth control through 10 days after the last Experimental Session.
- Must not participate in any other interventional clinical trials during the duration of the study
- Must be willing to remain overnight at the study site after each Experimental Session and be driven home after, and commit to medication dosing, therapy, and study procedures
- At baseline, meet DSM-5 criteria for current severe PTSD
Exclusion Criteria
- Are not able to give adequate informed consent
- Have uncontrolled hypertension
- Have a marked baseline prolongation of QT/QTc interval (e.g., repeated demonstration of a QTc interval >450 milliseconds [ms] in males and >460 ms in females corrected by Bazett's formula)
- Have a history of additional risk factors for Torsade de pointes (e.g., heart failure, hypokalemia, family history of Long QT Syndrome)
- Have evidence or history of significant medical disorders, such as myocardial infarction, cerebrovascular accident, or aneurysm
- Have symptomatic liver disease
- Have history of hyponatremia or hyperthermia
- Weigh less than 48 kilograms (kg)
- Are pregnant or nursing, or are of childbearing potential and are not practicing an effective means of birth control
- Have an active illicit or prescription drug use disorder
- Have used Ecstasy (material represented as containing MDMA) more than 10 times within the last 10 years or at least once within 6 months of the first Experimental Session; or have previously participated in a MAPS-sponsored MDMA clinical trial.
Primary Results(5 publications)
Participants
Adverse Events (from all publications)
| Arm / Group | n | Any TEAE | Severe | Serious | Discont. |
|---|---|---|---|---|---|
| MDMA-assisted therapyexperimental | 46 | — | — | 0(0.0%) | 1(2.2%) |
| Placebo with therapyplacebo | 44 | — | — | 2(4.5%) | 2(4.5%) |
| MDMA-assisted therapyexperimental | 42 | — | — | — | 3(7.1%) |
| Placebo with therapyplacebo | 40 | — | — | — | 4(10.0%) |
| MDMA-assisted therapyexperimental | 16 | — | — | — | — |
| Placebo with therapyplacebo | 7 | — | — | — | — |
| MDMA-assisted therapyexperimental | 46 | — | — | — | — |
| Placebo with therapyplacebo | 44 | — | — | — | — |
| MDMA-assisted therapyexperimental | 42 | — | — | — | 3(7.1%) |
| Placebo with therapyplacebo | 40 | — | — | — | 4(10.0%) |
* One participant discontinued due to being triggered by CAPS-5 assessments and an adverse event of depressed mood. AESIs (suicidality) included 3 participants (2 suicidal ideation, 1 intentional self-harm). No SAEs reported in MDMA arm.
* Two participants reported three SAEs (one suicide attempt, one suicidal ideation resulting in self-hospitalization). AESIs (suicidality) included 5 participants. Two participants discontinued due to adverse events (one discontinued intervention due to SAE, one withdrew due to adverse event).
* 3 participants in the MDMA arm withdrew from the study. Specific TEAE counts not provided in the text/tables provided.
* 4 participants in the Placebo group withdrew from the study. Specific TEAE counts not provided in the text/tables provided.
* This is a pilot sub-study of a larger Phase 3 trial. Safety/TEAE summary counts were not reported in the provided text/tables.
* Safety data summary not explicitly provided in the provided text/tables; text mentions 'acceptable safety profiles' in reference to previous Phase II trials.
* Safety data summary not explicitly provided in the provided text/tables.
* nAtRisk is the number of participants who completed both baseline and study termination assessments (N=42 for MDMA-AT). 3 participants in the MDMA group withdrew from the study.
* nAtRisk is the number of participants who completed both baseline and study termination assessments (N=40 for PT). 4 participants in the placebo group withdrew from the study.